© The Rockefeller University Press, 0022-1007/1998/11/1795/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 10, November 16, 1998 1795-1802
Mitogen-activated Protein Kinase Kinase Antagonized Fas-associated Death Domain Protein–mediated Apoptosis by Induced FLICE-inhibitory Protein Expression
Jung-Hua Yeh*,
,
Shu-Ching Hsu
,
,
Shou-Hwa Han*, and
Ming-Zong Lai*,
,
From the * Graduate Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11217, Taiwan; the
Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan; and the
Graduate Institute of Microbiology, National Taiwan University School of Medicine, Taipei 10018, Taiwan
Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3– induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.
Key Words: mitogen-activated protein kinase kinase Fas-associated death domain protein Fas FLIP apoptosis
Address correspondence to Ming-Zong Lai, Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan, Republic of China. Phone: 886-2-2789-9236; Fax: 886-2-2782-6085; E-mail: mblai{at}ccvax.sinica.edu.tw
This project was supported by grant DOH86-HR-508 from the Department of Health, grant NSC 86-2316-B001-012 M30 from the National Science Council, and a grant from Academia Sinica.
Abbreviations used: DR, death receptor; FADD, Fas-associated death domain protein; FLICE, FADD-like ICE; FLIP, FLICE-inhibitory protein; ICE, IL-1β–converting enzyme; MAPK, mitogen-activated protein kinase; MKK, MAPK kinase; nt, nucleotide(s); PI, propidium iodide; RT, reverse transcription.

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